title: CCR6 selectively promotes monocyte mediated inflammation and atherogenesis in mice.
abstract: The chemokine receptor CCR6 is expressed by various cell subsets implicated in atherogenesis, such as monocytes, Th17 and regulatory T cells. In order to further define the role of CCR6 in atherosclerosis, CCR6-deficient (Ccr6-/-) mice were crossed with low-density lipoprotein receptor-deficient (Ldlr-/-) mice to generate atherosclerosis-prone mice deficient in CCR6. Compared to Ldlr-/- controls, atherosclerotic burden in the aortic sinus and aorta were reduced in Ccr6-/-Ldlr-/- mice fed a high fat diet, associated with a profound depression in lesional macrophage accumulation. Local and systemic distributions of T cells, including frequencies of Th1, Th17 and regulatory T cells were unaltered. In contrast, circulating counts of both Gr-1(high) and Gr1(low) monocytes were reduced in Ccr6-/-Ldlr-/- mice. Moreover, CCR6 was revealed to promote monocyte adhesion to inflamed endothelium in vitro and leukocyte adhesion to carotid arteries in vivo. Finally, CCR6 selectively recruited monocytes but not T cells in an acute inflammatory air pouch model. We here show that CCR6 functions on multiple levels and regulates the mobilisation, adhesion and recruitment of monocytes/macrophages to the inflamed vessel, thereby promoting atherosclerosis, but is dispensable for hypercholesterolaemia-associated adaptive immune priming. Targeting CCR6 or its ligand CCL20 may therefore be a promising therapeutic strategy to alleviate atherosclerosis.
authors.affiliation: Univ.-Prof. Dr. Alma Zernecke, Klinikum rechts der Isar, Klinik für Gefäßchirurgie, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany, Tel: +49 89 4140 2167, Fax: +49 89 4140 4861, E-mail: zernecke@lrz.tum.de.
authors.forename: Helga D
authors.initials: HD
authors.lastname: Manthey
authors.forename: Clément
authors.initials: C
authors.lastname: Cochain
authors.forename: Stefanie
authors.initials: S
authors.lastname: Barnsteiner
authors.forename: Ela
authors.initials: E
authors.lastname: Karshovska
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Pelisek
authors.forename: Miriam
authors.initials: M
authors.lastname: Koch
authors.forename: Sweena M
authors.initials: SM
authors.lastname: Chaudhari
authors.forename: Martin
authors.initials: M
authors.lastname: Busch
authors.forename: Hans-Henning
authors.initials: HH
authors.lastname: Eckstein
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Rory R
authors.initials: RR
authors.lastname: Koenen
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology*; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D007249:Inflammation / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D054399:Receptors, CCR6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C106311:CCR6 protein, human; D054399:Receptors, CCR6; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; C551746:granulocyte receptor 1, mouse
keywords: Atherosclerosis; CCR6; chemokines; monocyte; recruitment